This invention pertains to compounds and processes which are useful for preparing herbicidal sulfonamides.
WO 95/27698-A1 discloses herbicidal sulfonamides for crop protection. There is a continuing need to develop compounds and processes useful for efficiently preparing these herbicidal sulfonamides.
This invention is directed to compounds and intermediates of Formulae 6 and 3, useful in preparing herbicidal sulfonamides of Formula 1, including all geometric and stereoisomers thereof, and agricultural salts thereof. 
wherein
X is H, F or Cl;
Y is F or Cl;
R1 is C1-C3 haloalkyl, C2-C4 alkoxyalkyl; C2-C6 haloalkoxyalkyl or C2 -C6 cyanoalkyl;
R2 is H, C1-C4 alkyl, C1-C4 haloalkyl, C3-C4 alkenyl, C3-C4 alkynyl, C2-C4 alkoxyalkyl, C2-C4 alkylcarbonyl or C2-C4 alkoxycarbonyl;
R3 is H or OH;
R4 is H, F or Cl; and
R5 is F or Cl;
provided that when R3 is H then R4 is F or Cl and when R3 is OH then R4 is H.
This invention is further directed to a process for preparing a compound of Formula I 
comprising halogenation of a compound of Formula 2a 
wherein the substituents are as first defined in the Summary of the Invention.
This invention is further directed to a process for preparing a compound of Formula 2
comprising cyclization of a compound of Formula 3
wherein the substituents are as first defined in the Summary of the Invention.
This invention is further directed to a process for preparing a compound of Formula 3
comprising reaction of a compound of Formula 5
with a compound of Formula 4
wherein the substituents are as first defined in the Summary of the Invention.
This invention is further directed to a process for preparing a compound of Formula 6
comprising a) reaction of a compound of Formula 8
with a compound of formula X1SO2R1 in the presence of a base to provide a compound of Formula 7; 
b) optional reaction of the compound of Formula 7 wherein R2 is H with X1R2 in the presence of a base to provide a compound of Formula 7 wherein R2 is other than H; and c) hydrolysis of the compound of Formula 7 with an acid or base to provide a compound of Formula 6;
wherein X1 is halogen, C2-C4 alkylcarbonyloxy, C1-C4 alkoxy, phenoxy, cyano or imidazolyl, and the remaining substituents are as first defined in the Summary of the Invention.
This invention is further directed to a process for preparing a compound of Formula 6a 
wherein a process sequence is selected from
A) a process sequence comprising a) reduction of a compound of Formula 12
to provide a compound of Formula 11
and b) chlorination of the compound of Formula 10 to provide a compound of Formula 6a;
wherein the substituents are as first defined in the Summary of the Invention; and
B) a process sequence comprising a) reduction of a compound of Formula 15
to provide a compound of Formula 14
and b) hydrolysis of the compound of Formula 14 to provide a compound of Formula 6a;
wherein the substituents are as first defined in the Summary of the Invention.
This invention is further directed to a process for preparing a compound of Formula I 
comprising a) cyclization of a compound of Formula 3
to provide the compound of Formula 2a 
and b) halogenation of the compound of Formula 2a to provide a compound of Formula 1 wherein R3 is OH, R4 is H, and the remaining substituents are as first defined in the Summary of the Invention.
This invention is further directed to a process for preparing a compound of Formula 2
comprising a) reaction of a compound of Formula 5
with a compound of Formula 4
to provide the compound of Formula 3
and b) cyclization of the compound of Formula 3 to a compound of Formula 2
wherein the substituents are as first defined in the Summary of the Invention.
This invention relates to compounds and intermediates for preparing herbicidal sulfonamides of Formula 1, including all geometric and stereoisomers thereof, and agricultural salts thereof.
The compounds and processes of this invention are illustrated below. The compounds of Formula 1 can be prepared via the processes of Steps 1-8 when R3 is OH. Alternatively, the compounds of Formula 1 can also be prepared via the processes of Steps 1-7 when R4 is F or Cl (compounds of Formula 2 wherein R4 is F or Cl are the same as compounds of Formula 1).
Further embodiments of the present invention are the alternative processes for preparing compounds of Formula 6a, which can be prepared by the processes of Steps 9-11 or by the processes of Steps 12-16. 
wherein
X is H, F or Cl;
Y is F or Cl;
R1 is C1-C3 haloalkyl, C2-C4 alkoxyalkyl, C2-C6 haloalkoxyalkyl or C2-C6 cyanoalkyl;
R2 is H, C1-C4 alkyl, C1-C4 haloalkyl, C3-C4 alkenyl, C3-C4 alkynyl, C2-C4 alkoxyalkyl, C2-C4 alkylcarbonyl or C2-C4 alkoxycarbonyl;
R3 is H or OH;
R4is H, F or Cl;
R5 is F or Cl; and
X1 is halogen, C2-C4 alkylcarbonyloxy, C1-C4 alkoxy, phenoxy, cyano or imidazolyl;
provided that when R3 is H then R4 is F or Cl and when R3 is OH then R4 is H.
Further processes of this invention to prepare intermediates of Formula 6a are illustrated below. 
wherein the definitions of X, X1, and R1 are as described above.
Further processes of this invention to prepare intermediates of Formula 6a are illustrated below. 
wherein X3 is OC(xe2x95x90O)CH3, halogen or C1-C4 alkoxy; and the definitions of X, X1, and R1 are as described above.
In the above recitations, the term xe2x80x9calkylxe2x80x9d, used either alone or in compound words such as xe2x80x9chaloalkylxe2x80x9d includes straight-chain or branched alkyl, such as, methyl, ethyl, n-propyl, i-propyl, or the different butyl, pentyl or hexyl isomers. xe2x80x9cAlkenylxe2x80x9d includes straight-chain or branched alkenes such as ethenyl, 1-propenyl, 2-propenyl, and the different butenyl, pentenyl and hexenyl isomers. xe2x80x9cAlkenylxe2x80x9d also includes polyenes such as 1,2-propadienyl and 2,4-hexadienyl. xe2x80x9cAlkynylxe2x80x9d includes straight-chain or branched alkynes such as ethynyl, 1-propynyl, 2-propynyl and the different butynyl, pentynyl and hexynyl isomers. xe2x80x9cAlkynylxe2x80x9d can also include moieties comprised of multiple triple bonds such as 2,5-hexadiynyl. xe2x80x9cAlkoxyxe2x80x9d includes, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy and the different butoxy, pentoxy and hexyloxy isomers. xe2x80x9cAlkoxyalkylxe2x80x9d denotes alkoxy substitution on alkyl. Examples of xe2x80x9calkoxyalkylxe2x80x9d include CH3OCH2, CH3OCH2CH2, CH3CH2OCH2, CH3CH2CH2CH2OCH2 and CH3CH2OCH2CH2. xe2x80x9cAlkylthioxe2x80x9d includes branched or straight-chain alkylthio moieties such as methylthio, ethylthio, and the different propylthio, butylthio, pentylthio and hexylthio isomers. xe2x80x9cCyanoalkylxe2x80x9d denotes an alkyl group substituted with one cyano group. Examples of xe2x80x9ccyanoalkylxe2x80x9d include NCCH2, NCCH2CH2 and CH3CH(CN)CH2.
The term xe2x80x9chalogenxe2x80x9d, either alone or in compound words such as xe2x80x9chaloalkylxe2x80x9d, includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as xe2x80x9chaloalkylxe2x80x9d, said alkyl may be partially or fully substituted with halogen atoms which may be the same or different. Examples of xe2x80x9chaloalkylxe2x80x9d include F3C, ClCH2, CF3CH2 and CF3CCl2. The terms xe2x80x9chaloalkoxyalkylxe2x80x9d, and the like, are defined analogously to the term xe2x80x9chaloalkylxe2x80x9d. Examples of xe2x80x9chaloalkoxyalkylxe2x80x9d include CF3OCH2, CCl3CH2OCH2, HCF2CH2CH2OCH2 and CF3CH2OCH2CH2.
The total number of carbon atoms in a substituent group is indicated by the xe2x80x9cCi-Cjxe2x80x9d prefix where i and j are numbers from 1 to 6. For example, C1-C3 alkylsulfonyl designates methylsulfonyl through propylsulfonyl; C2 alkoxyalkyl designates CH3OCH2; C3 alkoxyalkyl designates, for example, CH3CH(OCH3), CH3OCH2CH2 or CH3CH2OCH2; and C4 alkoxyalkyl designates the various isomers of an alkyl group substituted with an alkoxy group containing a total of four carbon atoms, examples including CH3CH2CH2OCH2 and CH3CH2OCH2CH2. Examples of xe2x80x9calkylcarbonylxe2x80x9d include C(O)CH3, C(O)CH2CH2CH3 and C(O)CH(CH3)2. Examples of xe2x80x9calkoxycarbonylxe2x80x9d include CH3OC(xe2x95x90O), CH3CH2OC(xe2x95x90O), CH3CH2CH2OC(xe2x95x90O), (CH3)2CHOC(xe2x95x90O) and the different butoxy- or pentoxycarbonyl isomers. Examples of xe2x80x9calkylcarbonyloxyxe2x80x9d include OC(O)CH3, OC(O)CH2CH2CH3 and OC(O)CH(CH3)2.
When a compound is substituted with a substituent bearing a subscript that indicates the number of said substituents can exceed 1, said substituents (when they exceed 1) are independently selected from the group of defined substituents. Further, when the subscript indicates a range, e.g. (R)i-j, then the number of substituents may be selected from the integers between i and j inclusive.
When a group contains a substituent which can be hydrogen, for example R2, then, when this substituent is taken as hydrogen, it is recognized that this is equivalent to said group being unsubstituted.
Preferred intermediates of Formula 3 for reasons of better activity and/or ease of synthesis are those wherein R2 is H and R1 is C1-C3 haloalkyl. Most preferred are the intermediates wherein R1 is CH2Cl.
Preferred intermediates of Formula 6 for reasons of better activity and/or ease of synthesis are those wherein R2 is H and R1 is C1-C3 haloalkyl. Most preferred are the intermediates wherein R1 is CH2Cl.
A preferred process for the preparation of a compound of Formula 1 for reasons of better activity and/or ease of synthesis is the process of Step 8 wherein R2 is H and R1 is C1-C3 haloalkyl. Most preferred is the process of Step 8 wherein X is F, Y is Cl, and R1 is CH2Cl.
A preferred process for the preparation of a compound of Formula 2 for reasons of better activity and/or ease of synthesis is the process of Step 7 wherein R2 is H and R1 is C1-C3 haloalkyl. Most preferred is the process of Step 7 wherein X is F, Y is Cl, and R1 is CH2Cl.
A preferred process for the preparation of a compound of Formula 3 for reasons of better activity and/or ease of synthesis is the process of Step 6 wherein R2 is H and R1 is C1-C3 haloalkyl. Most preferred is the process of Step 6 wherein X is F, Y is Cl, and R1 is CH2Cl.
A preferred process for the preparation of a compound of Formula 6 for reasons of better activity and/or ease of synthesis is the process comprising of Steps 3 and 4 wherein R2 is H, R1 is C1-C3 haloalkyl, and X1 is halogen. Most preferred is the process comprising of Steps 3 and 4 wherein X is F, Y is Cl, R1 is CH2Cl, and X1 is Cl.
A preferred process for the preparation of a compound of Formula 6a for reasons of better activity and/or ease of synthesis is the process comprising of Steps 10 and 11 wherein R1 is C1-C3 haloalkyl. Most preferred is the process comprising of Steps 10 and 11 wherein X is F and R1 is CH2Cl.
Another preferred process for the preparation of a compound of Formula 6a for reasons of better activity and/or ease of synthesis is the process comprising of Steps 15 and 16 wherein R1 is C1-C3 haloalkyl. Most preferred is the process comprising of Steps 15 and 16 wherein X is F and R1 is CH2Cl.
A preferred process for the preparation of a compound of Formula 1 for reasons of better activity and/or ease of synthesis is the process comprising of Steps 7 and 8 wherein R3 is OH, R2 is H, and R1 is C1-C3 haloalkyl. Most preferred is the process comprising of Steps 7 and 8 wherein X is F, Y is Cl, and R1 is CH2Cl.
A preferred process for the preparation of a compound of Formula 1 for reasons of better activity and/or ease of synthesis is the process comprising of Steps 6 and 7 wherein R2 is H and R1 is C1-C3 haloalkyl. Most preferred is the process comprising of Steps 6 and 7 wherein X is F, Y is Cl, and R1 is CH2Cl.
Step 1
Step 1 forms compounds of Formula 9 by reacting compounds of Formula 10 with a suitable nitrating agent. 
The reaction conditions for the nitration of Step 1 are well known in the art; see, for example, Houben-Weyl, Methoden der Organischen Chemie, Vol X/1 pp 479 and Vol. E 16 d, pp 262. Suitable nitrating agents include nitrogen (III) compounds (e.g., metal nitrites), nitrogen (V) compounds (e.g., metal nitrates, ammonium nitrates), nitronium compounds, nitric acid, fuming nitric acid, nitric acid in the presence of metal salts, nitric acid in the presence of inorganic acids, nitric acid in the presence of carboxylic acids such as glacial acetic acid or carboxylic acid anhydrides such as acetic anhydride, nitric acid in the presence of sulfonic acids, and nitric acid alkyl ethers. Additional nitrating reagents are described in the cited literature above. Preferred nitrating agents are fuming nitric acid or nitric acid in the presence of sulfuric acid. More preferred is the application of xe2x80x9cnitrating acidxe2x80x9d which is a mixture of nitric acid of different concentrations (68-100%) in the presence of concentrated sulfuric acid. Typical ratios range from 20% nitric acid:60% sulfuric acid:20% water up to 50% nitric acid:50% sulfuric acid. The most preferred ratio is equal amounts of fuming nitric acid and concentrated sulfuric acid. Nitrations may also be performed in inert solvents such as chlorocarbons, hydrocarbons, ethers or alcohols. Concentrated sulfuric acid or a mixture of concentrated sulfuric acid and oleum are preferred as solvents; most preferred is a mixture of concentrated sulfuric acid and oleum. Oleum containing between 20% and 65% sulfur trioxide can be applied. The optimum amount of oleum is that amount which traps the water which is generated during the reaction; thus, equimolar amounts of oleum and nitric acid are most preferred.
The nitrations can be performed at temperatures between xe2x88x9250 and 100xc2x0 C. Preferred temperatures are between xe2x88x9220 and 30xc2x0 C., with the most preferred reaction temperatures at xe2x88x925 to 5xc2x0 C.
Step 2
Step 2 forms compounds of Formula 8 by reacting compounds of Formula 9 with hydrogen in the presence of a hydrogenation catalyst or by reaction with other reducing agents. 
The reduction of compounds of Formula 9 in Step 2 can be achieved under well known hydrogenation conditions with metal catalysts such as Pt, Pd, Re, Rh, Ru, Ir, Ni, optionally with the use of promoters or accelerators. Non-catalytic reductions can be achieved, for example, with molar amounts of iron, iron salts, tin, tin salts, low valent sulfur compounds, lithium aluminum hydride, hydrazines, and other reducing agents as described in Houben-Weyl, Methoden der Organischen Chemie, Vol. II/1, p 360 and Vol. IV/2, p 506.
The catalytic hydrogenation can be performed in inert solvents such as alcohols, ethers, esters, ketones, amides or pyridine at temperatures between 0 and 160xc2x0 C. at atmospheric or elevated pressure between 100 and 10,000 kPa (1 and 100 atmospheres) in substrate:solvent dilutions between 1:1 and 1:100. Reducing agents such as hydrazines, unsaturated hydrocarbons such as cyclohexene or formic acid can be used in place of molecular hydrogen.
Preferably, the reaction is run with molecular hydrogen in the presence of an iridium catalyst in ethyl acetate at 100 to 10,000 kPa (1 to 100 atmospheres) pressure at temperatures between 30 and 120xc2x0 C. at concentrations of 0.01 to 5 M. More preferred is hydrogenation with molecular hydrogen at 200 to 6,000 kPa (2 to 60 atmospheres) of pressure, a temperature of 6590xc2x0 C. and concentrations of 0.2-1.0 M.
The reduction can also be achieved by the Bechamp method and variations thereof as described in Houben-Weyl, Methoden der Organischen Chemie, Vol II/1, p 394. The reaction can be run under neutral or acidic conditions in inert solvents such as esters, alcohols, aqueous alcohols, water, glacial acetic acid or hydrocarbons. Mineral acids (e.g., hydrochloric acid) or organic acids (e.g., acetic acid) can be used as acidic activators. The temperature may vary between 0xc2x0 C. and the boiling point of the solvent.
Preferred is the reduction in ethanol at temperatures between 30xc2x0 C. and the boiling point of the solvent with acetic acid as activator. The preferred molar ratio of substrate:acid:iron is 1:2-4:6-10.
The product can be isolated as a solid by removal of the catalyst by filtration and removal of the solvent by distillation. The solution can also be used directly in the next reaction. Preferably, the filtered solution is partially concentrated to a slurry and used directly in the next reaction.
Step 3
Step 3 forms compounds of Formula 7 (wherein R2 is H) by reacting compounds of Formula 8 with a sulfonyl halide of formula X1SO2R1 in the presence of a base. Optionally, compounds of Formula 7 (wherein R2 is other than H) are formed by reacting compounds of Formula 7 (wherein R2 is H) with compounds of R2X1 in the presence of a suitable base such as triethylamine, pyridine or N,N-dimethylaniline and optionally a suitable solvent such as a hydrocarbon, a halogenated hydrocarbon or an aromatic hydrocarbon. 
The sulfonamidation can be performed under well known conditions as described in Houben-Weyl, Methoden der Organischen Chemie, Vol IX, pp 609-614.
Preferably, the solution from Step 2 is concentrated to a slurry and used directly in the reaction of Step 3 by adding 1-100 molar equivalents of an organic or inorganic base, (preferred bases are organic bases such as pyridine, alkylpyridines or dialkylaminopyridines; most preferred is pyridine) and chloromethanesulfonyl chloride at xe2x88x9210 to 70xc2x0 C. Most preferred is the reaction of Step 3 wherein 7-13 equivalents of pyridine are added and the reaction temperature is initially in the range of 0 to 40xc2x0 C. and is later raised to 80 to 130xc2x0 C. The reaction proceeds in inert solvents such as esters, acetates, ketones, chlorocarbons, nitrites and pyridine. Preferred are ethyl acetate, pyridine or mixtures thereof; most preferred is pyridine. Alternatively, the reaction can be run at temperatures between 20 and 300xc2x0 C. without a base by heating the components in a solvent such as an ester, ketone, chlorocarbon or hydrocarbon or with a base under phase transfer conditions between 0 and 100xc2x0 C. as described in the literature (see, for example, C. M. Starks, C. L. Liotta, M. Halpern, Phase Transfer Catalysis, Chapman and Hall (1994) or DE patent 2,941,593), preferably with a ketone or chlorocarbon solvent. Most preferred solvents are methyl isobutyl ketone, dichloroethane, chloroform or methylene chloride.
Step 4
Step 4 forms compounds of Formula 6 by hydrolyzing the compounds of Formula 7 with acid or base. 
The crude reaction product of Formula 7 can be isolated by filtration; however, preferably the crude reaction product of Formula 7 is used directly without isolation in Step 4 by hydrolysis under basic or acidic conditions with mineral acids or inorganic bases at temperature between 30-120xc2x0 C. and a pressure of 100 kPa (1 atmosphere) or greater. Most preferred basic conditions include reaction temperatures of 50-55xc2x0 C. and 6 N NaOH. Most preferred acidic conditions include reaction temperatures of 90-110xc2x0 C. and 6 N HCl. Acidic hydrolysis is more preferred than basic methods of hydrolysis.
The product of Formula 6 can be recrystallized from organic solvents such as esters, ketones, aromatic hydrocarbons and chlorocarbons. Preferred is recrystallization from methyl isobutyl ketone, toluene or mixtures thereof.
Step 5
Step 5 forms compounds of Formula 5 by reacting compounds of Formula 6 with a phosgenating agent. 
The phosgenation of Step 5 can be performed by methods well known in the art (see, for example, Houben-Weyl, Methoden der Organischen Chemie, Vol. E 4) in aprotic organic solvents such as aliphatic hydrocarbons, aromatic hydrocarbons, aliphatic and aromatic chlorocarbons, chloroolefins, esters, ethers, ketones, nitrites, sulfones and nitroarenes at temperatures between xe2x88x9250 and 150xc2x0 C. with about 1 to 50 equivalents of a phosgenating agent such as phosgene, diphosgene, triphosgene, carbonyldiimidazole or carbamates from which the isocyanate is generated by elimination of alcohol. The phosgenation is preferably performed in a ketone or ether solvent, most preferably in methyl isobutyl ketone, or dimethoxyethane at temperatures between xe2x88x9250 and 150xc2x0 C., preferably between xe2x88x9210 and 80xc2x0 C., most preferably between 0 and 50xc2x0 C., with preferably about 1 to 10 equivalents of phosgene, and most preferably with 1.0 to 1.5 equivalents of phosgene.
Alternatively, the aniline of Formula 6 can be reacted with an alkali cyanate to give a urea intermediate which can be used for the following coupling Step 6.
Alternatively, the aniline of Formula 6 after the hydrolysis reaction of Step 4 can after neutralization be extracted directly into a suitable organic solvent, preferably a ketone or toluene, most preferably methyl isobutyl ketone, at room temperature or at an elevated temperature and used in the phosgenation of Step 5. By this means, water can be removed from the solution of a compound of Formula 6 by azeotropic distillation.
Step 6
Step 6 forms compounds of Formula 3 by reacting compounds of Formula 5 with compounds of Formula 4. 
Step 6 can be conducted in a single liquid phase which is a suitable solvent or it can be carried out in a two-phase system consisting of an aqueous phase and a suitable organic solvent. In the single phase coupling process, the compound of Formula 4 is suspended at 0-120xc2x0 C. in an organic solution consisting of an isocyanate of Formula 5 in a solvent such as a hydrocarbon, chlorocarbon, ether, ester, ketone, and preferably chlorobenzene, dichlorobenzene, dimethoxyethane, tetrahydorfuran or methyl isobutyl ketone.
Preferred solvents for the single phase process step are those toward which the isocyanate of Formula 5 is unreactive and which dissolve the compound of Formula 4 to the extent necessary for the reaction to proceed, and include ethers such as dimethoxyethane and tetrahydrofuran, esters such as ethyl acetate, or ketones such as acetone. Preferred reaction conditions include a temperature from about 0 to 100xc2x0 C., and a reaction time from about 30 minutes to 48 hours. More preferred are temperatures from about 20 to 40xc2x0 C. and reaction times from 2 hours to 24 hours. Particularly preferred for achieving high yields of compounds of Formula 3 is the process wherein the solvent is tetrahydrofuran. Also preferred for this process is the use of an excess of the compound of Formula 4, which excess can be removed by filtration once the reaction is complete, providing a solution of the product of Formula 3. Optionally, this product can be further purified by extraction into aqueous alkali, acidification of the aqueous solution, and isolation of the product of Formula 3 by filtration or by extraction into a suitable organic solvent.
More preferred is a two-phase system wherein the organic solution of the isocyanate of Formula 5 is added to the compound of Formula 4 or a suitable salt thereof dissolved in aqueous base, preferably sodium hydroxide. The aqueous phase has a concentration between 0.1 and 10 M and contains 1 to 10 equivalents of the compound of Formula 4 with 1 to 10 equivalents of base with respect to the compound of Formula 4. It is preferred to run the reaction at concentrations between 0.5 and 5 M, and most preferred between 1 and 3 M. 1-5 equivalents of the compound of Formula 4 are preferred; most preferred is 1 to 1.5 equivalents. Solvents such as ketones, chlorobenzene, dichlorobenzene and dimethoxyethane and mixtures thereof are preferred, with ketones such as methyl isobutyl ketone being most preferred. The coupling reaction is done at temperatures between xe2x88x9215 and 100xc2x0 C., preferably between xe2x88x9210 and 40xc2x0 C.
Suitable organic solvents for the two-phase process include halocarbons such as chloroform or dichloromethane, esters such as ethyl acetate, or ketones such as methyl isobutyl ketone. The aqueous phase is a solution of the compound of Formula 4 or a suitable salt thereof and a base, preferably sodium hydroxide. The two phases are contacted at a temperature of about xe2x88x9210 to about 50xc2x0 C., preferably at about 0xc2x0 C. After completion of the reaction and separation of the aqueous phase, the aqueous phase is acidified with mineral acid and the product of Formula 3 can be isolated by filtration or extracted into a suitable organic solvent.
In the two-phase coupling step the pH is adjusted to between 7.5 and 4.5, preferably to about pH 6-7 and the organic layer removed. The aqueous solution of Step 6 is further acidified to about pH 0 to 4, preferably about pH 2, and extracted with an organic solvent such as a hydrocarbon, chlorocarbon, ester, or ketone, preferably with the same solvent as used in the preceding Step 5, most preferably methyl isobutyl ketone.
The product can be isolated from the organic phase by distilling off the solvent or by precipitation. Alternatively, the organic phase can be optionally dried with a suitable material such as sodium sulfate or magnesium sulfate or by azeotropic distillation. Most preferred is to use the product of Step 6 directly in the next reaction Step 7.
Compounds of Formula 4 wherein R3 is H and R4 is F or Cl, i.e., trans-4-fluoro-D-proline or trans-4-chloro-D-proline, can be made from the compound of Formula 4 wherein R3 is OH and R4 is H, cis-4-hydroxy-D-proline, by first protecting the carboxylic acid and amino functions with suitable protecting groups or other derivatives, followed by reacting this protected compound with a halogenating agent such as those described in the references listed within, optionally after converting the hydroxyl function to a leaving group, and finally removing the protecting groups. Appropriate choices of protecting groups or other derivatives and leaving groups and methods for their application will be apparent to one skilled in the art. Syntheses of the enantiomeric compounds trans-4-fluoro-L-proline and trans4-chloro-L-proline are described in Biochemistry (1965) 4, 2507 and in Aust. J. Chem. (1967) 20, 1493, respectively.
Step 7
Step 7 forms compounds of Formula 2 by reacting compounds of Formula 3 with a cyclizing agent. 
The cyclizing agent of Step 7 can be an acid or any suitable reagent for cyclizing the activated form of compounds of Formula 3. Suitable reagents for cyclizing thus include alkylchloroformates in the presence of an acid or a base, carbodiimides or anhydrides. The cyclization of the compounds of Formula 3 can proceed in organic solvents such as chlorocarbons, esters, ethers, ketones or nitriles. The cyclization can also be induced by allowing the solution of compound of Formula 3 to stand at room temperature or, preferably, thermally by heating the compound of Formula 3 in a solvent such as methyl isobutyl ketone at 100 kPa (1 atmosphere) or elevated pressure. Preferred cyclization conditions are the addition of 0.01-10 equivalents of a strong acid such as hydrochloric acid, phosphoric acid, acetic acid, trifluoroacetic acid or a strong xe2x80x9csolid acidxe2x80x9d, or cyclization with dicyclohexyl carbodiimide in the presence of N-hydroxysuccinimide.
The most preferred cyclization conditions include 0.5-2 equivalents of concentrated sulfuric acid in methyl isobutyl ketone at 0-120xc2x0 C. Thus, the product of the previous Step 6 as an aqueous solution of the compound of Formula 3 at pH 6 is further acidified to pH 2-3 and extracted into an organic solvent, most preferred methyl isobutyl ketone. From this solution water can optionally be removed by azeotropic distillation. The compound of Formula 3 is then cyclized to the compound of Formula 2 by the addition of 0.01-10 equivalents of a strong acid such as hydrochloric acid, phosphoric acid, acetic acid, or trifluoroacetic acid, most preferably 0.5-1 equivalent of concentrated sulfuric acid, at 0-120xc2x0 C., most preferably in refluxing methyl isobutyl ketone.
In addition to the reagents and reaction conditions detailed above, compounds of Formula 3 wherein R4 is F or Cl can also be cyclized to compounds of Formula 2 wherein R4 is F or Cl by converting the carboxylic acid function of the compound of Formula 3 to an activated form by a further number of methods known to the skilled artisan. These activated forms include (a) acid halides, obtained by treatment of compounds of Formula 3 with thionyl chloride, oxalyl chloride or equivalent reagents; (b) mixed anhydrides, obtained by treatment of compounds of Formula 3 with phosgene, alkyl chloroformates, phosphoryl chlorides, acetic anhydride or equivalent reagents; and (c) activated esters, obtained by treatment of compounds of Formula 3 with dicyclohexylcarbodiimide and N-hydroxysuccinimide or equivalent reagents. The preferred process is reaction of a compound of Formula 3 with thionyl chloride in a suitable solvent at a temperature of about 0 to 100xc2x0 C., with a reaction time of about 30 minutes to 48 hours. Suitable solvents for this preferred process include halocarbons such as chloroform, dichloromethane or dichloroethane, ethers such as tetrahydrofuran or dimethoxyethane, esters such as ethyl acetate, ketones such as acetone or methyl isobutyl ketone, or other aprotic solvents such as acetonitrile. Also preferred is the use of a catalyst such as pyridine or N,N-dimethylformamide. Most preferred is the process with dichloromethane as solvent, at a temperature of about 20 to 40xc2x0 C., with a reaction time of about 2 to 24 hours. The product of Formula 2 can be isolated from the reaction mixture by evaporating the volatiles, replacing the dichloromethane with a solvent in which the product has less solubility, and filtration. Alternatively, the crude product can be converted to a salt by treatment with, e.g., an amine compound. After isolating this salt, the product of Formula 2 can be liberated by treating the salt with a mineral acid.
Step 8
Step 8 forms compounds of Formula 1 by reacting compounds of Formula 2a with a halogenating agent in a suitable solvent. 
The halogenating agent is a chlorinating agent such as thionyl chloride or phosphorous pentachloride, or a fluorinating agent such as diethylaminosulfur trifluoride, sulfur tetrafluoride or a fluorinated amine reagent. Other fluorinating agents include those described in Tetrahedron (1993) 49, 9385; Aldrichimica Acta (1993) 26, 47; Tetrahedron Letters (1989) 30, 3077; Tetrahedron Letters (1995) 36, 2611; and Tetrahedron (1996) 52, 2977. For the process of Step 8, the temperature is from about 0 to 200xc2x0 C., the pressure is from about 100 to about 500 kPa (1 to about 5 atmospheres) and the reaction time is from about 1 minute to 24 hours. Suitable solvents include halocarbons such as chloroform, dichloromethane, dichloroethane, fluorobenzene, benzotrifluoride, chlorobenzene, or dichlorobenzene; hydrocarbons such as benzene, toluene, or xylene and fluoroderivatives thereof; ethers such as diphenyl ether, dioxane or dimethoxyethane; esters such as n-propyl acetate or isobutyl acetate; ketones such as methyl isobutyl ketone, 4-heptanone or cyclohexanone; or nitriles such as acetonitrile or benzonitrile. The molar ratio of the compound of Formula 2a to the halogenating agent is typically from about 1:1 to 1:5.
Preferred are processes wherein the halogenating agent is a fluorinated amine reagent of formula R6R7NCF2CFHR8, the temperature is from about 30 to 180xc2x0 C., and the molar ratio of the compound of Formula 2a to halogenating agent is from about 1:1 to 1:2. R6 and R7 are independently C1-C10alkyl or branched alkyl groups such as methyl, ethyl or isopropyl, or they may be taken together to form a ring such as xe2x80x94CH2(CH2)3CH2xe2x80x94 or xe2x80x94CH2(CH2)4CH2xe2x80x94; R8 is a halogen such as chlorine or fluorine, or R8 is a C1-C4 haloalkyl group such as trifluoromethyl. These fluorinated amine reagents may be prepared by methods described in Bull. Chem. Soc. Japan (1979) 52, 3377 or modifications thereof. Other methods of preparation include the reaction of an olefin with a dialkylamine, for example the reaction of hexafluoropropene with diethylamine, or the reaction of a fluoro-olefin such as chlorotrifluoroethylene, tetrafluoroethylene or other polyfluorinated olefin with an alkylamine, dialkylamine, or cyclic amine.
Most preferred are processes wherein the halogenating agent is a fluorinated amine reagent of formula R6R7NCF2CFHR8, where R6 and R7 are each independently methyl or ethyl, and R8 is fluoro or trifluoromethyl. Most preferred reaction conditions include a temperature of about 40 to 120xc2x0 C., a pressure of about 100 to about 200 kPa (1 to 2 atmospheres), and a reaction time of about 1 minute to 4 hours in a solvent which is dichloromethane, chloroform, chlorobenzene, fluorobenzene, toluene or isopropyl acetate. The molar ratio of the compound of Formula 2a to the halogenating agent is from about 1:1.0 to 1:1.2, and the reaction vessel is constructed of a material which is substantially unreactive with the fluorinating agent and hydrogen fluoride under the reaction conditions.
The product of Formula 1 can be isolated from the reaction mixture in various ways. In some cases, the compound of Formula 1 can be crystallized from the reaction mixture, and can be isolated by filtration, optionally after removal of volatile by-products and some portion of the reaction solvent by distillation and/or extraction with water. It can also be advantageous to crystallize the compound of Formula 1 from a suitable solvent, optionally with removal of some or all volatile by-products and reaction solvent by distillation and/or extraction with water. Suitable solvents for crystallization of the compound of Formula 1 include, but are not limited to, alcohols such as methanol, ethanol, n-propanol, i-propanol, i-butanol, amyl alcohol, cyclohexanol or 1-heptanol; ketones such as methyl isobutyl ketone or cyclohexanone; ethers such as diphenyl ether or methyl tert-butyl ether; halocarbons such as dichloroethane, trichloroethane, chlorobenzene, dichlorobenzene, fluorobenzene or benzotrifluoride; and hydrocarbons such as toluene or xylene, including mixtures and aqueous mixtures thereof. Alternatively, it is sometimes more convenient to convert the compound of Formula 1 to a salt by treatment with, for example, an amine compound, and to first isolate this salt by filtration. The product of Formula 1 can then be liberated by treating this salt with a mineral acid.
Step 9
Step 9 forms compounds of Formula 12 by reacting compounds of Formula 13 with a sulfonyl halide of formula X1SO2R1 in the presence of a base. 
The sulfonamidation can be performed under well known conditions as described in Houben-Weyl, Methoden der Organischen Chemie, Vol IX, pp 609-614.
Preferably, the reaction of Step 9 employs 1-100 molar equivalents of an organic or inorganic base, (preferred bases are organic bases such as pyridine, alkylpyridines or dialkylaminopyridines; most preferred is pyridine) and chloromethanesulfonyl chloride at xe2x88x9210 to 70xc2x0 C. The reaction proceeds in inert solvents such as esters, acetates, ketones, chlorocarbons, nitriles and pyridine. Preferred solvents are ethyl acetate, pyridine or mixtures thereof; most preferred is pyridine. Alternatively, the reaction can be run at temperatures between 20 and 300xc2x0 C. without a base by heating the components in a solvent such as an ester, ketone, chlorocarbon or hydrocarbon or with a base under phase transfer conditions between 0 and 100xc2x0 C. as described in the literature (see, for example, C. M. Starks, C. L. Liotta, M. Halpern, Phase Transfer Catalysis, Chapman and Hall (1994), or DE patent 2,941,593), preferably with a ketone or chlorocarbon solvent. Most preferred solvents are methyl isobutyl ketone, dichloroethane, chloroform or methylene chloride.
Step 10
Step 10 forms compounds of Formula 11 by reacting compounds of Formula 12 with hydrogen in the presence of a hydrogenation catalyst or by reaction with other reducing agents. 
The reduction of compounds of Formula 12 in Step 10 can be achieved under well known hydrogenation conditions with metal catalysts such as Pt or Pd, optionally with the use of promoters or accelerators. Non-catalytic reductions can be achieved, for example, with molar amounts of iron, iron salts, tin, tin salts, low valent sulfur compounds, lithium aluminum hydride, hydrazines, and other reducing agents as described in Houben-Weyl, Methoden der Organischen Chemie, Vol. II/1, p 360 and Vol. IV/2, p 506.
The catalytic hydrogenation can be performed in inert solvents such as alcohols, ethers, esters, ketones, amides or pyridine at temperatures between 0 and 160xc2x0 C. and at a pressure between 100 and 10,000 kPa (1 and 100 atmospheres) in substrate:solvent dilutions between 1:1 and 1:100. Reducing agents such as hydrazines, unsaturated hydrocarbons such as cyclohexene or formic acid can be used in place of molecular hydrogen.
The reduction can also be achieved by the Bechamp method and variations thereof as described in Houben-Weyl, Methoden der Organischen Chemie, Vol II/1, p 394. The reaction can be run under neutral or acidic conditions in inert solvents such as esters, alcohols, aqueous alcohols, water, glacial acetic acid or hydrocarbons. Mineral acids (e.g., hydrochloric acid) or organic acids (e.g., acetic acid) can be used as acidic activators. The temperature may vary between 0xc2x0 C. and the boiling point of the solvent.
Preferred is the reduction in ethanol at temperatures between 30xc2x0 C. and the boiling point of the solvent with acetic acid as activator. The preferred molar ratio of substrate:acid:iron is 1:2-4:6-10.
The product can be isolated as a solid by removal of the catalyst by filtration and removal of the solvent by distillation.
Step 11
Step 11 forms compounds of Formula 6a by reacting compounds of Formula 11 with a chlorinating agent. 
Chlorinating agents include N-chlorosuccinimide, thionyl chloride, phosphorous pentachloride or chlorine gas. For the process of Step 11, the temperature is from about 0 to 200xc2x0 C., the pressure is from about 100 to about 500 kPa (1 to about 5 atmospheres) and the reaction time is about 1 minute to 24 hours. Suitable solvents include halocarbons such as chloroform, dichloromethane, dichloroethane, chlorobenzene or dichlorobenzene, hydrocarbons such as benzene, toluene or xylene, and other solvents such as dimethylformamide. The molar ratio of the compound of Formula 11 to the halogenating agent is typically from 1:1 to 1:1.2.
The preferred chlorinating reaction conditions are N-chlorosuccinimide in dimethylformamide at a temperature of 50xc2x0 C. The molar ratio of the compound of Formula 11 to N-chlorosuccinimide is 1:1.1.
The product can be isolated by diluting the reaction with ethyl acetate and washing with water. Separation of the organic layer and removal of the solvent by distillation provides a product which can be purified by crystallization using appropriate solvents such as a chlorobutane/ether mixture, or by flash chromatography eluting with an appropriate hydrocarbon solvent mixture such as hexane and ethyl acetate.
Step 12
Step 12 forms compounds of Formula 17 by reacting compounds of Formula 18 with a sulfonyl halide of formula X1 SO2R1 in the presence of a base. The sulfonamidation can be done under conditions well known in the art; see, for example, Houben-Weyl, Methoden der Organischen Chemie, Vol. IX, pp 609-614. 
Compounds of Formula 18 can be reacted with a sulfonyl halide of formula X1SO2R1 in a variety of inert organic solvents such as aliphatic and aromatic hydrocarbons, heteroarenes, halocarbons, esters, ketones and nitrites in the presence of organic bases such as mono-, di- and tri-alkylamines or, preferably, aromatic amines such as pyridines, alkylpyridines and dialkylpyridines, or inorganic bases such as sodium or potassium bicarbonate, sodium, potassium, lithium and magnesium carbonate. When an organic base is used, the reaction can also be run under conditions where the base serves as the solvent.
The preferred procedure consists of running the reaction of Step 2 in toluene or acetone, at temperatures between xe2x88x9230 and 50xc2x0 C., most preferably at 5 to 10xc2x0 C. The sulfonyl chloride is added to the solution such that the temperature does not exceed 10 to 15xc2x0 C. After the addition is complete, the mixture is stirred an additional 30 minutes followed by the addition of 0.5 to 4 equivalents of an organic base, preferably 2 equivalents of triethylamine, at 5 to 10xc2x0 C.
Step, 13
Step 13 forms compounds of Formula 16 by reacting compounds of Formula 17 with an acetylating agent of formula CH3C(xe2x95x90O)X3, wherein X3 is OC(xe2x95x90O)CH3, halogen or C1-4 alkoxy. 
The compound of the Formula 17 can be acetylated under conditions well known in the art using a suitable carboxylic acid or a carboxylic acid derivative such as an anhydride, acyl halide or ester, optionally in the presence of a base. The preferred reaction conditions include reaction of the compound of Formula 17 with acetic anhydride at temperatures between xe2x88x9240 and 140xc2x0 C. in a suitable inert solvent. Most preferably, the compound of Formula 17 is treated with acetic anhydride at a temperature of between 20xc2x0 C. and reflux; the acetic anhydride serves as a solvent and as the acylating agent simultaneously.
Step 14
Step 14 forms compounds of Formula 15 by reacting compounds of Formula 16 with a nitrating agent. 
The reaction conditions for the nitration of Step 14 are well known in the art; see, for example, Houben-Weyl, Methoden der Organischen Chemie, Vol. X/1 p 479, and Vol. E 16d, p 262. The reaction conditions are as previously described for the nitration of the compound of Formula 10 in Step 1. Preferred reaction conditions are performing the reaction at 0-15xc2x0 C. with 30% SO3 dissolved in concentrated sulfuric acid in combination with a xe2x80x9cnitrating acidxe2x80x9d made from equal amounts of concentrated sulfuric acid and fuming nitric acid.
Step 15
Step 15 forms compounds of Formula 14 by reacting compounds of Formula 15 with a reducing agent. 
The compound of Formula 15 can be reduced to the compound of Formula 14 with reducing agents such as described in Houben-Weyl, Methoden der Organischen Chemie, Vol. II/1 p 360; also, see the reduction conditions described in Step 2. Alternatively, and preferably, the reduction is done in the presence of a metal catalyst by molecular hydrogen or hydrogen equivalents as described in Houben-Weyl, Methoden der Organischen Chemie, Vol. IV/2, p 506; also, see the reduction conditions described in Step 2. In the most preferred procedure, an iridium catalyst on carbon or a nickel catalyst is applied in ethanol at temperatures between 0 and 150xc2x0 C. under a hydrogen pressure of 100 to 10,000 kPa (1 to 100 atmospheres).
Step 16
Step 16 forms compounds of Formula 6a by the hydrolysis of compounds of Formula 14. 
The conversion of a compound of Formula 14 to a compound of Formula 6a can be done under acidic or basic conditions in inert solvents in which the compound of Formula 14 is sufficiently soluble, at temperatures between 0xc2x0 C. and the refluxing solvent. It is preferred to dissolve the starting material in a suitable alcohol, preferably ethanol, and to add aqueous sodium hydroxide as a base. The hydrolysis can then be done between room temperature and the refluxing solution, most preferably at 45-55xc2x0 C.
It is recognized that some reagents and reaction conditions described above for preparing compounds of Formulae 1-17 may not be compatible with certain functionalities present in the intermediates. In these instances, the incorporation of protection/deprotection sequences or functional group interconversions into the synthesis will aid in obtaining the desired products. The use and choice of the protecting groups will be apparent to one skilled in chemical synthesis (see, for example, Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York (1991).
One skilled in the art will recognize that, in some cases, after the introduction of a given reagent as it is depicted in any individual scheme, it may be necessary to perform additional routine synthetic steps not described in detail to complete the synthesis of compounds of Formulae 1-17.
One skilled in the art will also recognize that it may be necessary to perform a combination of the steps illustrated in the above schemes in an order other than that implied by the particular sequence presented to prepare the compounds of Formulae 1-17.
One skilled in the art will also recognize that compounds of Formulae 1-17 and the intermediates described herein can be subjected to various electrophilic, nucleophilic, radical, organometallic, oxidation, and reduction reactions to add substituents or modify existing substituents.
Without further elaboration, it is believed that one skilled in the art using the preceding description can utilize the present invention to its fullest extent. The following Examples are, therefore, to be construed as merely illustrative, and not limiting of the disclosure in any way whatsoever. Percentages are by weight except for chromatographic solvent mixtures or where otherwise indicated. Parts and percentages for chromatographic solvent mixtures are by volume unless otherwise indicated. 1H NMR spectra are reported in ppm downfield from tetramethylsilane; s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, dd=doublet of doublets, dt=doublet of triplets, br s=broad singlet. HPLC is high pressure liquid chromatography. HPLC purity is area percentage.
Structures 3a and 1a are shown below to illustrate the Chemical Abstracts system of atom numbering and stereochemical designations used in the following examples. 